Benzyl Alcohol → Benzyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochloride

HRID 30512

Reaction equation

HRID 30512 reaction equation
[CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(Cl)([Cl:23])=O.C1CCC(CN)(CC(O)=O)CC1.Cl>C(OCC)C>[ClH:23].[NH2:12][CH2:11][C:4]1([CH2:7][C:8]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1

Participants

6

Reactant 4

HCID 244Benzyl AlcoholHCID 3446GabapentinHCID 24386Thionyl Chloride3×HCID 6453919Gabapentin hydrochloride4×

Product 1

HCID 70673669Benzyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochlorideYield 91%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
0 °C

Procedure

A dry 500 mL, three-necked, round-bottomed flask was fitted with a magnetic stirring bar and a 60 mL pressure-equalizing addition funnel and flushed with nitrogen gas. The flask was charged with gabapentin (17.1 g, 0.1 mol) and benzyl alcohol (128 mL, 1.18 mol) and the mixture was cooled to 0° C. with an ice-water bath. Thionyl chloride (51.8 mL, 77.25 g, 0.65 mol) was added dropwise to the stirred solution over a period of 1 h. The reaction was monitored by LC/MS, with product and unreacted gabapentin hydrochloride being observed. After stirring at room temperature for 3.5 days the reaction mixture contained residual gabapentin hydrochloride (by LC/MS). Additional thionyl chloride (20 mL, 30 g, 0.25 mol) was added at 0° C., and the reaction mixture allowed to stir at room temperature for another 12 h (LC/MS shows traces of residual gabapentin hydrochloride). A final portion of thionyl chloride (10 mL, 15 g, 0.12 mol) was added at 0° C. and the reaction mixture allowed to stir at room temperature for 4 h (LC/MS showed no remaining gabapentin hydrochloride). The reaction mixture was then diluted with ethyl ether (200 mL) and cooled to 0° C. while stirring. White crystalline solid formed, which was collected by filtration. The crude compound was recrystallized from a mixture of ethanol and ethyl ether (50 mL: 150 mL.) Finally the white crystals were washed with 250 mL of ethyl acetate to give product (6) as a white solid (27 g, 91% yield). 1H NMR (CDCl3, 400 MHz.): δ 1.43-1.52 (m, 10H), 2.64 (s, 2H), 3.08 (d, 2H), 6.04 (br. s, 1H), 7.25-7.33 (m, 5H), 8.44 (br. s, 3H). MS (ESI) m/z 262.26 (M+H+).

Workup

  1. customA dry 500 mL, three-necked, round-bottomed flask was fitted with a magnetic stirring bar and a 60 mL pressure-equalizing addition funnel
  2. customflushed with nitrogen gas
  3. stirringto stir at room temperature for 4 h (LC/MS
  4. temperaturecooled to 0° C.
  5. stirringwhile stirring
  6. customWhite crystalline solid formed
  7. filtrationwhich was collected by filtration
  8. customThe crude compound was recrystallized from a mixture of ethanol and ethyl ether (50 mL: 150 mL.) Finally the white crystals
  9. washwere washed with 250 mL of ethyl acetate

Sources & evidence

ORD record
ord-ff95fa76aa7942059c0be08e6bf74b99
Source dataset
uspto-grants-2008_09
Patent number
US07423169B2

Linked notes

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